title: Rapid and specific targeting of monoclonal antibody A33 to a colon cancer xenograft in nude mice.
abstract: Monoclonal antibody (mAb) A33 detects a glycoprotein homogeneously expressed by > 95% of human colon cancers and by normal colon cells. The A33 antigen is not secreted or shed and after mAb A33 binds to antigen on the cell membrane, a fraction of membrane-bound mAb A33 is internalized into endosomes. Phase I 131I-mAb A33 biodistribution studies have shown consistent, specific tumor-targeting, and phase I radioimmunotherapy trials with 131I- or 125I-mAb A33 have demonstrated antitumor effects. Here we describe a nude mouse model that was established using a human colon cancer cell line, SW1222, which grows as a relatively hypovascular, invasive heterotransplant when injected i.m. Peak uptake of 131I-labeled or 111In-chelated mAb A33 was observed at 48-96 h, with a mean of 34% (SE +/- 5.0) and 46.7% (SE +/- 1.7) injected dose per gram of tumor tissue, respectively. 111In-mAb A33 was retained in tumor tissue longer than halide radioimmunoconjugates. The specificity of antibody localization was assessed using a control antibody (tumor uptake and pharmacokinetics), a control tumor, corrections for vascular antibody blood-pooling in tumor tissue, and blocking of radiolabeled mAb A33 localization by pretreating mice with excess unlabeled mAb A33. These experiments demonstrate that mAb A33 localization in tumor was specific, and they emphasize the unexpected rapidity with which the antibody localizes. Our conclusions were confirmed by immunohistochemical techniques which allowed direct visualization of localization and distribution of the humanized version of mAb A33 in tumor tissue. Furthermore, antibody doses approximating tumor-saturating doses demonstrated that a homogeneous distribution of antibody in tumor is possible. This model will be valuable for studies focusing on general physiologic aspects of antibody-to-tumor cell localization and critical as a guide to the evaluation of various A33 antibody constructs and combinations with other therapies for the treatment of colon cancer.
authors.affiliation: Ludwig Institute for Cancer Research, Heidelberg, Victoria, Australia.
authors.forename: E C
authors.initials: EC
authors.lastname: Barendswaard
authors.forename: A M
authors.initials: AM
authors.lastname: Scott
authors.forename: C R
authors.initials: CR
authors.lastname: Divgi
authors.forename: C
authors.initials: C
authors.lastname: Williams
authors.forename: K
authors.initials: K
authors.lastname: Coplan
authors.forename: E
authors.initials: E
authors.lastname: Riedel
authors.forename: T J
authors.initials: TJ
authors.lastname: Yao
authors.forename: O A
authors.initials: OA
authors.lastname: Gansow
authors.forename: R D
authors.initials: RD
authors.lastname: Finn
authors.forename: S M
authors.initials: SM
authors.lastname: Larson
authors.forename: L J
authors.initials: LJ
authors.lastname: Old
authors.forename: S
authors.initials: S
authors.lastname: Welt
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics*; D000912:Antibodies, Neoplasm / Q000494:pharmacology*; D000951:Antigens, Neoplasm / Q000276:immunology*; D003110:Colonic Neoplasms / Q000378:metabolism*; D005260:Female; D006801:Humans; D007205:Indium Radioisotopes; D007457:Iodine Radioisotopes; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000378:metabolism*; D016719:Radioimmunodetection / Q000379:methods; D014018:Tissue Distribution; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D000951:Antigens, Neoplasm; C104258:GPA33 protein, human; C504395:Gpa33 protein, mouse; D007205:Indium Radioisotopes; D007457:Iodine Radioisotopes; D008562:Membrane Glycoproteins